Drug delivery systems are developed to lower therapeutic doses, increase residence time, and prolong release over time of drugs to targeted tissues. Toxic effects of drugs can be minimized when uptake by untargeted organs is reduced. Targeting allows delivery of relatively high levels of drug to a focal site, minimizing systemic complications and lowering costs of therapy. Liposomes are self assembly vesicles made from phospholipids and cholesterol that have been widely used in targeted drug delivery applications including cancer therapy, gene delivery, and thrombolysis (Lasic, D. D., Liposomes: From Physics to Applications. Amsterdam, the Netherlands: Elsevier, 1993, pp 31-32.) since their discovery almost forty years ago (Bangham, A. D. et al., “Diffusion of univalent ions across the lamellae of swollen phospholipids,” J. Mol. Bio. vol. 13, pp. 238-252, 1965.). Vesicles made from synthetic non ionic surfactants (niosomes) are analogous to liposomes. Niosomes have also been used as drug encapsulating vesicles showing advantages over liposomes, including greater chemical stability, lower cost, easier storage and handling, and less potential for toxicity (Uchegbu, I. F. et al., “Non-ionic surfactant vesicles (niosomes): physical and pharmaceutical chemistry.” Adv. Colliod. Interfac., vol. 58, no. 1, pp. 1-55, 1995.). As drug delivery vesicles, niosomes have been shown to enhance absorption of some drugs across cell membranes (Lasic, D. D., 1993, pp 31-32), to localize in targeted organs (Jain, C. P. et al., “Preparation and characterization of niosomes containing rifampicin for lung targeting,” Microencapsulation, vol. 12 no. 4, pp. 401-407, 1995; Namdeo, A. J. et al., “Niosomal delivery of 5-fluoruoracil,” J. Microencapsulation, vol. 16, no. 6, pp. 731-740, 1999.) and tissues (Baille, A. J. et al., “Non-ionic surfactant vesicles, niosomes, as delivery system for the anti-leishmanial drug, sodium stribogluconate,” J. Pharm. Pharacol., vol. 38, pp. 502-505, 1986; Azmin, M. N., et al., “The effect of non-ionic surfactant vesicle (niosome) entrapment on the absorption and distribution of methotrexate in mice,” J. Pharm. Pharmacol., vol. 37, pp. 237-242, 1985.), and to elude the reticuloendothelial system (Gopinath, D. et al., “Pharmocokinetics of zidovudine following intravenous bolus administration of a novel niosome preparation devoid of cholesterol.,” A. F. Drug Research, vol. 51, no. 11, pp. 924-930. November, 2001).
The administration of small molecules such as liposomes or niosomes to a subject can occur in a variety of ways including by catheter. Catheters are generally devices that can be inserted into a subject, particularly within tubular structures such as blood vessels, the digestive tract, the urinary tract, the reproductive tract, etc. The general structure of a catheter is well known in the art. A catheter generally has a tubular main body that is flexible and has at least one lumen extending therethrough. A port may be located at one end of the catheter for injection of vesicles such as niosomes into the subject. Attaching an ultrasound imaging probe to a catheter has the advantage of allowing the visualization of the interior walls of a tubular structure of a subject in order to provide guided and targeted delivery of a small molecule, such as a niosome containing a therapeutic or diagnostic compound, to a specific area of the subject Immunoniosomes, such as those described in U.S. Published Patent Application No. 2007/0172520 herein incorporated by reference, may be used to induce an antibody/ligand reaction to allow the niosome to adhere to specific target cells. As defined in the above referenced U.S. Patent Application, immunoniosomes are defined as a niosome bearing an antibody or antibody fragment that acts as a targeting moiety enabling the niosome to specifically bind to a particular target molecule that may exist in solution or may be bound to the surface of a cell.
Ultrasound enhanced drug delivery has several important advantages in that it is noninvasive, can be carefully focused and controlled and can penetrate deep into the body. Early uses of ultrasound to aid drug delivery were transcutaneous. The technique for using ultrasound to drive drug molecules across the percutaneous barrier to a targeted area, or ‘phonophoresis’, was developed fifty years ago, and is itself a field of research (Ng, K. et al., “Therapeutic ultrasound: its application in drug delivery,” Med. Res. Rev., vol. 22, no. 2, pp. 204-223, 2002.). Other drug therapies shown to be enhanced by ultrasound include chemotherapy, thrombolytics, and gene delivery. Drug targeting and localized release has been shown to enhance uptake by tumor cells when encapsulated by polymeric micelles subjected to focused ultrasound at therapeutic levels (Rapoport, N. Y. et al., “Ultrasound-triggered drug targeting of tumors in vitro and in vivo,” Ultrasonics, vol. 42, pp. 943-950, 2004). Low intensity ultrasound has been shown to enhance the permeabilization of liposomes with polyethylene glycol head groups (Lin, H. Y. et al., “PEG-Lipids and oligo(ethylene glycol) surfactants enhance the ultrasonic permeabilizability of liposomes,” Langmuir, vol. 19, pp. 1098-1105, 2003; Baillie, A. J., et al., “The preparation and properties of niosome—non-ionic surfactant vesicles,” J. Pharm. Pharmacol., vol. 37, pp. 863-868, 1985.).
Effective targeted drug delivery can be achieved in many instances through release of therapeutic agents in a more controlled manner than possible with passive diffusion across a bilayer membrane. Controlled release of a drug from a specifically targeted vesicle to a site using ultrasound can be optimized through the tuning of transducer frequency, beam distance and focus, and absolute and peak power delivered to the vesicle suspension. The lipid bilayers that make up liposomes and niosomes are similar to biological membranes in that they are able to self-repair when perturbed. Sonication is widely used to reduce large multilamellar vesicles to smaller unilamellar ones. Control of membrane permeability via ultrasound would have many therapeutic applications especially when coupled with the active and passive drug targeting possible with lipid membrane vesicles. To this end, a technique for making non ionic surfactant vesicles and the use and effect of exposure to clinical levels of ultrasound to achieve release of the drug model is taught herein.